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Biotech / Medical : RNAi -- Ignore unavailable to you. Want to Upgrade?

To: bob zagorin who wrote (86)	9/10/2003 12:40:47 PM
From: tuck	Read Replies (2) \| Respond to of 671

[Off-target effects update] >>Nat Cell Biol. 2003 Sep;5(9):834-9. Epub 2003 Aug 24. Activation of the interferon system by short-interfering RNAs. Sledz CA, Holko M, De Veer MJ, Silverman RH, Williams BR. [1] Department of Cancer Biology, Lerner Research Institute, NB40, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 USA. [2] Molecular Virology Program, Case Western Reserve University, Cleveland, OH 44106, USA. RNA interference (RNAi) is a powerful tool used to manipulate gene expression or determine gene function. One technique of expressing the short double-stranded (ds) RNA intermediates required for interference in mammalian systems is the introduction of short-interfering (si) RNAs. Although RNAi strategies are reliant on a high degree of specificity, little attention has been given to the potential non-specific effects that might be induced. Here, we found that transfection of siRNAs results in interferon (IFN)-mediated activation of the Jak-Stat pathway and global upregulation of IFN-stimulated genes. This effect is mediated by the dsRNA-dependent protein kinase, PKR, which is activated by 21-base-pair (bp) siRNAs and required for upregulation of IFN-beta in response to siRNAs. In addition, we show by using cell lines deficient in specific components mediating IFN action that the RNAi mechanism itself is independent of the interferon system. Thus, siRNAs have broad and complicating effects beyond the selective silencing of target genes when introduced into cells. This is of critical importance, as siRNAs are currently being explored for their potential therapeutic use.<< But in the link in your post (thanks for that!), Williams and others downplay this issue, and say delivery is the big one. As I had speculated earlier, designing the siRNA to the optimal sequence to limit the off-target effects is doable (see the Tuschl interview). Further, Williams notes that while the interferon system is present in all humans, it is not usually a pathway found to be functional for tumor cell lines, so it's not a problem in every therapeutic area. Cheers, Tuck

To: bob zagorin who wrote (86)	9/10/2003 4:18:07 PM
From: michael_f_murphy	Read Replies (1) \| Respond to of 671

RNAi company list from the free issue. Alnylam Cambridge, Mass. Private John Maraganore, president, CEO, & director; Tom Ulich, senior vice president of R&D Developing RNAi-based drugs with a focus on viral, oncologic, metabolic, CNS, and autoimmune diseases. Ambion Austin, Texas Private Matt Winkler, CEO & CSO; Bruce Leander, president Sells RNAi oligos, research products, and reagents. Atugen Berlin Private Klaus Giese, CSO; Thomas Christély, COO & CFO Developing RNAi-based drugs with a focus on cancer; also provides drug discovery and validation services. Benitec Brisbane, Australia Public (Australia) John McKinley, chairman & CEO; Ken Reed, director of research & technology Developing RNAi-based drugs for HIV/AIDS, cancer, hepatitis, diabetes, cardiomyopathies, autoimmune, and CNS diseases. BD Biosciences Clontech Palo Alto, Calif. Unit of publicly held Becton, Dickinson Sailaja Kuchibhatla, vice president of business development Sells instrumentation, research products, and reagents. Cenix BioScience Dresden, Germany Private Christophe Echeverri, CEO & CSO Sells siRNAs through a collaboration with Ambion; also provides drug discovery and validation services. CytRx Los Angeles Public Steven Kriegsman, president & CEO; David Haen, director of business development Developing RNAi-based drugs for obesity, type II diabetes, and ALS. Dharmacon Lafayette, Colo. Private Stephen Scaringe, co-chairman & CSO Sells RNAi oligos, research products, and reagents. Genta Berkeley Heights, NJ Public Raymond Warrell, chairman & CEO; Robert Klem, vice president of discovery & CTO Developing RNAi-based cancer drugs. Intradigm Rockville, Md. Private John Spears, chairman & CEO; Martin Woodle, CSO Developing RNAi-based cancer drugs. Nucleonics Malvern, Pa. Private Robert Towarnicki, president & CEO; C. Satishchandran, vice president of R&D; Cathy Pachuk, senior director of biological research Developing RNAi-based drugs for hepatitis B and C. Proligo Boulder, Colo. Unit of publicly held (Germany) Degussa Klaus Puell, CEO; Bruno Poddevin, vice president of Primers and Probes division Sells RNAi oligos, instrumentation, research products, and reagents. Promega Madison, Wis. Private William Linton, president, & CEO; Richard Schifreen, director of technology and market development Sells instrumentation, research products, and reagents. Qiagen Venlo, Netherlands Public Metin Colpan, CEO & managing director; Detlev Riesner, supervisory board chairman & supervisory director Sells RNAi oligos, research products, and reagents. Sequitur Natick, Mass. Private Tod Woolf, president & CEO; Margaret Taylor, vice president of research Developing RNAi-based drugs, with a focus on hepatic insufficiency, RSV, asthma, breast cancer; also provides drug discovery and validation services, as well as research products and reagents. Sirna Boulder, Colo. Public Howard Robin, president & CEO; Nassim Usman, CSO & vice president of R&D Developing RNAi-based drugs for hepatitis C and age-related macular degeneration.